RESUMEN
Alloxan diabetes was modeled in August rats with high activity of the NO system and in Wistar rats, and the effects of NO system blockade (by a course treatment with L-NNA) on Langerhans islet ß cells were studied in 15 days. The toxic effects of diabetes on the rat ß cells and islets were similar: the content of active ß cells in the islets decreased to 15-20%, the number of islets to 24-29% of control. A course of L-NNA reduced the ß cell and islet death, in August cells greater than in Wistar: the number of islets in August rats was restored to 81%, in Wistar rats to 60% of initial level; the activity of ß cells remained at the control level in the former and 2-fold lower than in the control in the latter. It seems that a less pronounced protective effect of L-NNA in Wistar rats was explained by excessive reduction of NO level essential for ß cell regeneration.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Islotes Pancreáticos/patología , Óxido Nítrico/metabolismo , Nitroarginina/farmacología , Animales , Pesos y Medidas Corporales , Recuento de Células , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/efectos de los fármacos , Islotes Pancreáticos/crecimiento & desarrollo , Masculino , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Polidipsia/prevención & control , Ratas , Ratas Endogámicas , Ratas Wistar , Estadísticas no ParamétricasRESUMEN
UNLABELLED: The mechanisms of the protective effect of oligonucleotides (OGN) during pathological processes are poorlyunderstood. The goal of this work was to study the effect of OGN on arrhythmias induced by myocardial ischemia and reperfusion, and the HSP70 level in the heart. As a source of OGN was used the drug "Derinat" ("Technomedservis", Russia). In male Wistar rats were pre-treated the drug for 7 days (i/m, 7.5 mg/kg).The intensity of the arrhythmias was assessed by ECG during 10 min occlusion of the left coronary artery and subsequent 5 min of reperfusion. Protein HSP70 determined in the left ventricle of the heart by Western-blot analysis. During ischemia, this drug reduced duration of extrasystolia by 13 times and the incidence of ventricular tachycardia by 1.5 times. During reperfusion the drug reduced the incidence of ventricular fibrillation, a more than 2-fold, as compared with the control (respectively 23% vs 56%) and by 5 times its duration (8,4 ± 2,3 48,1 ± sec vs 18 7 sec). "Derinat" increased the HSP70 level in the heart by 65% compared with control. CONCLUSION: These data support the fact that the activation of HSP70 synthesis, induced by OGN is one of the mechanisms that increases the heart resistance to the ischemic and reperfusion damages.
Asunto(s)
Antiarrítmicos/farmacocinética , Arritmias Cardíacas , Proteínas HSP70 de Choque Térmico/biosíntesis , Miocardio , Oligonucleótidos/farmacología , Animales , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocardio/metabolismo , Miocardio/patología , Ratas Wistar , Factores de TiempoRESUMEN
Previously we have shown that adaptation to hypoxia (AH) is cardio- and vasoprotective in myocardial ischemic and reperfusion injury and this protection is associated with restriction of nitrosative stress. The present study was focused on further elucidation of NO-dependent mechanisms of AH by identifying specific NO synthases (NOS) that could play the major role in AH protection. AH was performed in a normobaric hypoxic chamber by breathing hypoxic gas mixture (9.5-10% O2) for 5-10 min with intervening 4 min normoxia (5-8 cycles daily for 21 days). Expression of neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) protein was measured in the left ventricular myocardium using Western blot analysis with respective antibodies. AH educed iNOS protein expression by 71% (p < 0.05) whereas eNOS protein expression tended to be reduced by 41% compared to control (p < 0.05). nNOS protein expression remained unchanged after AH. Selective iNOS inhibition can mimic the AH-induced protection. Therefore protective effects of AH could be at least partially due to restriction of iNOS and, probably, eNOS expression.
Asunto(s)
Adaptación Fisiológica , Regulación Enzimológica de la Expresión Génica , Hipoxia/enzimología , Miocardio/enzimología , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Óxido Nítrico Sintasa de Tipo I/biosíntesis , Animales , Masculino , RatasRESUMEN
We studied the effects of N(w)-nitro-L-arginine (L-NNA), a nonselective inhibitor of NO synthases, on the severity of type 1 diabetes mellitus induced by subcutaneous injection of 130 mg/kg alloxan in August rats with high activity of NO system and in Wistar rats. Five days after alloxan injection, hyperglycemia levels after overnight fasting in August and Wistar rats were 27.1±3.7 and 22.0±1.1 mmol/liter, respectively (p<0.03). The mortality over 15 days after alloxan injection in August rats was higher than in Wistar rats (36 and 26%, respectively). L-NNA normalized glucose levels in diabetics of both groups. It completely prevented mortality in August and reduced it to 13% in Wistar rats. Body weight loss and polydipsia after L-NNA injection were also less pronounced in August rats. Plasma nitrite/nitrate concentrations in August rats were 32% higher than in Wistar rats, both in intact and diabetic rats. These data attest to an important role of NO in the pathogenesis of alloxan diabetes.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/prevención & control , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico/fisiología , Nitroarginina/uso terapéutico , Aloxano , Animales , Glucemia/análisis , Inhibidores Enzimáticos/uso terapéutico , Masculino , Nitratos/sangre , Óxido Nítrico/biosíntesis , Nitritos/sangre , Ratas , Ratas Endogámicas , Ratas WistarRESUMEN
Adaptation to hypoxia is known to be cardioprotective in ischemic and reperfusion (IR) injury of the myocardium. This study was focused on investigating a possibility for prevention of endothelial dysfunction in IR injury of the rat heart using adaptation to intermittent hypoxia, which was performed in a cyclic mode (5-10 min of hypoxia interspersed with 4 min of normoxia, 5-8 cycles daily) for 21 days. Endothelial function of coronary blood vessels was evaluated after the in vitro IR of isolated heart (15 min of ischemia and 10 min of reperfusion) by the increment of coronary flow rate in response to acetylcholine. Endothelium-dependent relaxation of isolated rat aorta was evaluated after the IR myocardial injury in situ (30 min of ischemia and 60 min of reperfusion) by a relaxation response of noradrenaline-precontracted vessel rings to acetylcholine. The following major results were obtained in this study: 1) IR myocardial injury induced endothelial dysfunction of coronary blood vessels and the aorta, a non-coronary blood vessel, remote from the IR injury area; and 2) adaptation to hypoxia prevented the endothelial dysfunction of both coronary and non-coronary blood vessels associated with the IR injury. Therefore, adaptation to hypoxia is not only cardioprotective but also vasoprotective in myocardial IR injury.
Asunto(s)
Adaptación Fisiológica , Hipoxia/fisiopatología , Daño por Reperfusión Miocárdica/fisiopatología , Acetilcolina/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/fisiopatología , Circulación Coronaria , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiopatología , Endotelio Vascular/fisiopatología , Masculino , Norepinefrina/farmacología , Ratas , Ratas Wistar , VasodilataciónRESUMEN
Previously, we have shown that nitric oxide (NO) plays an important role in the pathogenesis of alloxan diabetes (ALD). In this study in August rats, with the congenital increased activity of NO, and in Wistar rats was induced ALD (130 mg/kg, p/c) and 15 days after were examined the effects of the NO-blockade synthesis, induced by administration of Nω-nitro-L-arginine (L-NNA) cour- se on the activity of lipid peroxidation (LP), HIF-1α level, the degree of NO-system activation. The activation of iNOS, HIF-1a expression and 3-nitrotyrosine accumulation in liver were more pronounced in August-ALD rats than in Wistar-ALD rats. The level of TBA-active products in the heart and liver was increased in both diabetic groups only in the first 3 days ofALD and then this indicator of LP sharply was decreased as compared with the control. This effect was pronounced more in August rats. The inhibition of NO overproduction reduced significantly the severity of ALD and prevented the activation of LP, iNOS and HIF-1a. Thus, these data suggest, that NO plays an important role in the pathogenesis of ALD and in the regulation of oxygen homeostasis.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Inhibidores Enzimáticos/farmacología , Hígado/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Animales , Diabetes Mellitus Experimental/patología , Regulación de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Peroxidación de Lípido/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Ratas , Ratas Endogámicas , Ratas Wistar , Especificidad de la Especie , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
Adaptation to intermittent normobaric hypoxia is cardioprotective and can stimulate nitric oxide (NO) synthesis. However the role of nitric oxide (NO) in prevention of ischemia-reperfusion (IR) injury of myocardium is controversial. This study was focused on evaluating the effect of adaptation to hypoxia and IR on NO production and development of nitrative stress in the myocardium. Adaptation to hypoxia tended to increase NO production, which was determined by the total level of plasma nitrite and nitrate, and prevented IR-induced NO overproduction. The IR-induced NO overproduction was associated with significant 3-nitrotyrosine (3-NT) accumulation in the left ventricle but not in septum or aorta. In hypoxia-adapted rats, 3-NT after IR was similar to that of control rats without IR. IHC induced marked accumulation of HIF-1alpha in the left ventricle. We suggest that HIF-1alpha contributes to NO-synthase expression during adaptation to hypoxia and thereby facilitates the increase in NO production. NO, in turn, may subsequently prevent NO overproduction during IR by a negative feedback mechanism.
Asunto(s)
Ventrículos Cardíacos/metabolismo , Hipoxia/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Óxido Nítrico/metabolismo , Tirosina/análogos & derivados , Animales , Ventrículos Cardíacos/fisiopatología , Hipoxia/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Óxido Nítrico Sintasa/metabolismo , Ratas , Ratas Wistar , Tirosina/metabolismoRESUMEN
Similar degree of glycemia (28-31 mmol/liter) and similar mortality (37-42%) were revealed in August rats exhibiting enhanced activity of NO system and in Wistar rats 3 weeks after alloxan treatment. Under conditions of myocardial ischemia caused by 10-min coronary artery ligation, the intensity of arrhythmias did not differ from the control in Wistar rats with diabetes mellitus and increased in August rats. Under conditions of reperfusion, diabetes produced an antiarrhythmic effect in Wistar rats and did not affect arrhythmia in August rats. Plasma concentrations of nitrates and nitrites in Wistar and August rats increased by 82 and 143%, respectively, compared to the control. The level of hemoxygenase-1 (hsp32) in the myocardium remained unchanged in Wistar rats and decreased by 26% in August rats. Thus, the absence of antiarrhythmic effect of acute diabetes in August rats is probably related to elevated NO content and reduced antioxidant activity.
Asunto(s)
Arritmias Cardíacas/etiología , Arritmias Cardíacas/metabolismo , Diabetes Mellitus Experimental/complicaciones , Óxido Nítrico/metabolismo , Daño por Reperfusión/complicaciones , Animales , Western Blotting , Hemo Oxigenasa (Desciclizante)/metabolismo , Miocardio/metabolismo , Nitratos/sangre , Nitritos/sangre , Ratas , Ratas Endogámicas , Ratas Wistar , Estadísticas no ParamétricasRESUMEN
UNLABELLED: Heart function was studied in the August rats with innate raised sympathetic-adrenal system and in the Wistar rats through the period of 3 month after myocardial infarction. The sizes of the postinfarction scars were similar in the rats under comparison (56-62%) but end-diastolic pressure in Wistar rats and in August rats was 18.7 +/- 2.2 mm Hg and 11.8 +/- 0.7 mm Hg. Under the maximum isometric load induced by the aorta coarctation, the work efficiency of the heart in the August rats was greater than in the Wistar rats. During the postinfarction period, plasma catecholamine (CA) in August rats was higher than in Wistar rats. In the adrenal glands, the CA contents in August rats increased and in Wistar rats decreased. The activity of CA resynthes in the adrenal glands and in the hypothalamus in August rats did not change and in Wistar rats increased. The blood contents of nitrate and nitrite and hemine oxygenase-1 level in the myocardium of August rats were increased in contrast to Wistar rats. THE CONCLUSION: the higher viability of the myocardium in August rats with long existing postinfarction cardiasclerosis is to a considerable extent associated with lowered activation of the sympathetic-adrenal system under more expressing activation of NO-system and antioxidant protection.
Asunto(s)
Glándulas Suprarrenales/fisiopatología , Corazón/fisiopatología , Hipotálamo/fisiopatología , Infarto del Miocardio/fisiopatología , Glándulas Suprarrenales/metabolismo , Animales , Aorta/metabolismo , Aorta/fisiopatología , Presión Sanguínea , Catecolaminas/sangre , Cicatriz/sangre , Cicatriz/fisiopatología , Pruebas de Función Cardíaca , Hipotálamo/metabolismo , Infarto del Miocardio/sangre , Miocardio/metabolismo , Ratas , Ratas Endogámicas , Ratas Wistar , Especificidad de la Especie , Factores de TiempoRESUMEN
Study on a model of 6-day dosed adaptation to heat in rats showed that this adaptation decreased the severity of cardiac arrhythmias during ischemic and reperfusion injury. The duration of arrhythmias decreased not only in the ischemic period, but also under conditions of reperfusion. Adaptation delayed the development of arrhythmias during ischemia, decreased the number of animals with late reperfusion arrhythmias, and improved recovery of the heart after ischemia and reperfusion.
Asunto(s)
Adaptación Fisiológica , Arritmias Cardíacas/fisiopatología , Calor , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/fisiopatología , Animales , Arritmias Cardíacas/metabolismo , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Óxido Nítrico/biosíntesis , Ratas , Factores de TiempoRESUMEN
Three months after myocardial infarction the severity of heart failure and size of postinfarction scars in August rats with inherently reduced adrenoreactivity of the myocardium were similar to those in Wistar rats. The mortality rate in August rats was 2.5-fold lower than in Wistar rats. During the postinfarction period, myocardial adrenoreactivity in August rats remained lower, while the efficiency of cardiac function was 62% higher than in Wistar rats. The incidence of epinephrine-induced arrhythmias in August rats was much lower than in Wistar rats.
Asunto(s)
Infarto del Miocardio/fisiopatología , Receptores Adrenérgicos beta/fisiología , Animales , Catecolaminas/metabolismo , Epinefrina , Infarto del Miocardio/complicaciones , Ratas , Ratas Endogámicas , Ratas Wistar , Esclerosis/etiología , Especificidad de la EspecieRESUMEN
Total power of heart rate variability and baroreflex sensitivity were significantly smaller in the August rats than in the Wistar rats, but adrenal and plasma catecholamine contents were considerably higher in the former ones. 1 hour after stress (30 min in cold water), plasma catecholamine was increased 2-fold in Wistar rats, while in August rats the adrenaline concentration increased only by 58% and the were no changes in noradrenaline content. At the same time, activation of catecholamine metabolism in the adrenal glands was similar in both groups. The oxidative stress induced by hydrogen peroxide depressed the contractile function of isolated heart in the August rats to a smaller extent as compared to Wistar rats, control ones and after the cold-water stress. This effect correlated with more pronounced stability ofantioxidant enzymes in the August rats. It seems that the greater resistance to stress damage in the August rats is mediated by enhanced power of defense mechanisms both at systemic and cellular levels.
Asunto(s)
Corteza Suprarrenal/metabolismo , Barorreflejo , Presión Sanguínea , Catecolaminas/metabolismo , Frecuencia Cardíaca , Estrés Oxidativo , Estrés Psicológico/metabolismo , Animales , Catecolaminas/sangre , Frío , Inmersión , Inmovilización , Técnicas In Vitro , Ratas , Ratas Endogámicas , Ratas Wistar , Especificidad de la Especie , Estrés Psicológico/fisiopatologíaRESUMEN
Analysis of contribution of sympathetic and parasympathetic systems into heart rate variability carried out using atenolol and atropine showed that August rats are characterized by enhanced tone of the sympathetic system and reduced tone of the parasympathetic system compared to Wistar rats. Reduced tone of the parasympathetic system is also confirmed by lower sensitivity of the baroreflex. Blockade of NO synthesis with Nw-nitro-L-arginine more markedly increased blood pressure variability in August rats compared to Wistar rats. The data attest to a certain rigidity of the autonomic cardiovascular regulation in August rats.
Asunto(s)
Sistema Nervioso Autónomo/fisiología , Presión Sanguínea , Frecuencia Cardíaca , Antagonistas Adrenérgicos beta/farmacología , Animales , Atenolol/farmacología , Atropina/farmacología , Sistema Nervioso Autónomo/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Sistema Nervioso Parasimpático/efectos de los fármacos , Sistema Nervioso Parasimpático/fisiología , Ratas , Ratas Wistar , Especificidad de la Especie , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiologíaRESUMEN
In August rats, local myocardial ischemia caused by 30-min occlusion of the coronary artery induced a slight depression of the contractile function of the heart; the latter was restored after 15-min reperfusion more rapidly than in Wistar rats. In August rats, the activities of antioxidant protection enzymes were lower than in Wistar rats. In comparison with Wistar rats, these enzyme activities were decreased in a lesser degree under ischemia and were restored in a greater degree under reperfusion. It may thus be concluded that the higher stability of antiradical protection parameters in August rats is one of the mechanisms responsible for the enhanced resistance of the heart to ischemia- and reperfusion-induced injuries.
Asunto(s)
Contracción Miocárdica/fisiología , Miocardio/enzimología , Daño por Reperfusión/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Catalasa/metabolismo , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas , Ratas Wistar , Daño por Reperfusión/enzimología , Especificidad de la Especie , Superóxido Dismutasa/metabolismo , Xantina Oxidasa/metabolismoRESUMEN
In August rats reperfusion after regional myocardial ischemia in situ or intracoronary administration of hydrogen peroxide less significantly suppressed contractile activity of the heart compared to Wistar rats. Activities of catalase and superoxide dismutase in the myocardium during reperfusion remained unchanged in August rats. In Wistar rats a profound inhibition of cardiac function was accompanied by a decrease in enzyme activity.
Asunto(s)
Contracción Miocárdica/fisiología , Daño por Reperfusión Miocárdica/enzimología , Miocardio/enzimología , Estrés Oxidativo/genética , Superóxido Dismutasa/metabolismo , Animales , Catalasa/metabolismo , Corazón/efectos de los fármacos , Corazón/fisiología , Peróxido de Hidrógeno/farmacología , Técnicas In Vitro , Masculino , Contracción Miocárdica/efectos de los fármacos , Reperfusión Miocárdica , Daño por Reperfusión Miocárdica/fisiopatología , Ratas , Ratas Endogámicas , Ratas WistarRESUMEN
Power spectral density of heart rate fluctuations in the range of 0.02-5.00 Hz in August rats was lower than in Wistar rats. Changes in mean blood pressure and heart rate during stress (15-min immobilization) were similar in animals of both strains. As differentiated from Wistar rats, power spectral density of fluctuations in August rats considerably decreased after stress. August rats were characterized by low spectral power at rest and high resistance to the arrhythmogenic effect of 10-min acute myocardial ischemia.
Asunto(s)
Isquemia Miocárdica/patología , Animales , Arritmias Cardíacas/patología , Masculino , Ratas , Ratas Wistar , Especificidad de la Especie , Estrés Fisiológico , Sistema Nervioso Simpático/patología , Factores de TiempoRESUMEN
As differentiated from Wistar rats, myocardial ischemia and reperfusion produce no ventricular fibrillation in August rats. Pretreatment with nitric oxide synthase inhibitor Nw-nitro-L-arginine increased mortality rate in August rats with acute myocardial infarction from 20 to 40%. Under these conditions mortality rate in Wistar rats increased from 50 to 71%. Interstrain differences in the resistance of these animals to the arrhythmogenic effect of ischemia are probably associated with higher activity of the nitric oxide system in August rats compared to Wistar rats.
Asunto(s)
Arritmias Cardíacas/etiología , Isquemia Miocárdica/complicaciones , Daño por Reperfusión Miocárdica/complicaciones , Ratas Endogámicas , Ratas Wistar , Animales , Inhibidores Enzimáticos/farmacología , Masculino , Isquemia Miocárdica/mortalidad , Daño por Reperfusión Miocárdica/mortalidad , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/efectos de los fármacos , Nitroarginina/farmacología , Ratas , Especificidad de la EspecieRESUMEN
Accumulation of HSP70 stress proteins in the myocardium and blood content of nitrite/nitrate in August rats with modeled myocardial infarction surpassed these parameters in Wistar rats less resistant to cardiovascular disorders by 2-2.5 and 1.8 times, respectively. Our results suggest that various resistance of August and Wistar rats to myocardial infarction is related to genetically determined differences in the activity of HSP70 and nitric oxide systems.
Asunto(s)
Proteínas HSP70 de Choque Térmico/biosíntesis , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Óxido Nítrico/metabolismo , Animales , Predisposición Genética a la Enfermedad , Masculino , Miocardio/metabolismo , Nitratos/sangre , Óxido Nítrico/biosíntesis , Nitritos/sangre , Ratas , Ratas Endogámicas , Ratas Wistar , Especificidad de la EspecieRESUMEN
In intact August rats, the cardiac contractile function at rest was by 76% higher than in Wistar rats, while their hearts, both intact and after acute myocardial infarction, were more resistant to isometric load than the hearts of Wistar rats. Postinfarction mortality in August rats was 18% vs. 70% in Wistar rats. Adrenoreactivity of the myocardium in August rats was decreased compared to that in Wistar rats. These peculiarities can determine high resistance of August rats to myocardial infarction.
Asunto(s)
Infarto del Miocardio/genética , Infarto del Miocardio/fisiopatología , Animales , Predisposición Genética a la Enfermedad , Contracción Miocárdica/genética , Isquemia Miocárdica/genética , Isquemia Miocárdica/fisiopatología , Ratas , Ratas Endogámicas , Ratas Wistar , Especificidad de la EspecieRESUMEN
A lesser resistance against myocardial infarction (MI) in the Wistar rats as compared with the August rats was found to be combined with a greater stress-response and activation of the heart sympathetic regulation in the former rats. In the Wistar rats and not in August rats, an activation of hypothalamic noradrenaline (NA) system occurs as well as a greater "output" of the NA from sympathetic terminals in the myocardium. Accumulation of the HSP 70 stress-proteins in IM in the myocardium is nearly 2-2.5-fold lesser in the Wistar rats. Thereupon, different resistance against the IM in Wistar and August rats seems to be due to a genetically determine differences in intensity of the stress-response, activation of the heart sympathetic regulation in the IM, and production of the HSP 70 protective stress-proteins in the myocardium.